The main goal of this project is to develop stand-alone implantable glucose sensors and self-regulating insulin delivery devices based on sol-gel phase-reversible hydrogels. The specific aims of this project are geared to testing the following two hypotheses: (I) insulin delivery can be controlled as a (linear) function of the glucose concentration in the environment using glucose-specific phase-reversible hydrogels; and (ii) biocompatible glucose-specific molecules (or glucose receptors) can be synthesized mimicking the alignments of amino acids in several glucose-specific protein molecules. The three specific aims are: (1) to develop advanced phase-reversible hydrogels (initially based on concanavalin A (Con-A)) sensitive to glucose in the range of 0.5 mg/ml to 5 mg/ml; (2) to synthesize new glucose receptors; and (3) to develop glucose-specific hydrogels based on artificial glucose receptors. The main methodology include synthesis of various glucose-containing copolymers, artificial glucose receptors using combinatorial chemistry, and glucose-sensitive phase-reversible hydrogels using polymeric glucose receptors. The glucose affinity of synthesized glucose receptor candidates (based on cyclodextrins) will be examined by HPLC, equilibrium dialysis, surface plasmon resonance, and NMR. The glucose-specific phase-reversible hydrogels will be used for glucose sensing and modulated insulin release. This study is novel in that the sol-gel phase-reversible hydrogels have a potential to be used as a stand-alone, implantable glucose sensor and as a self-regulating insulin delivery device. In addition, we will be the first group to explore the synthesis of novel glucose binding molecules using combinatorial chemistry. The importance of this research is that it will provide a new synthetic glucose receptors and glucose-specific hydrogels, and thus will lay the foundation for the development of clinically useful glucose sensor and insulin delivery devices.